The lactone form of camptothecin and nearly all derivatives thereof are highly lipophilic, poorly water soluble compounds (HLCDs). Typically, less than 5 micrograms of the lactone form of CPT (and many of its derivatives) will dissolve in 1 milliliter of water. The carboxylate form of CPT, with its opened E-ring has a much greater water solubility. However, the carboxylate form of the drug possesses much lower antineoplastic activity and has exhibited higher toxicity when administered to patients with cancer.
Due to the poor water solubility of lactone CPT and derivatives, which limits the ability to readily administer HLCDs in a clinically practical manner, a great deal of research has been conducted to develop lactone CPT derivatives which possess greater water solubility. This research has produced compounds such as CPT-11 (7-ethyl-10-4-(1-piperidino)-1-piperidino! carbonyloxy camptothecin also referred to as Irinotecan or Camptosar.TM.), which was approved for use in the United States in 1996, and Topotecan (9-dimethylaminomethyl-10-hydroxy camptothecin), also recently approved for use as a cancer chemotherapeutic agent.
CPT-11 is a water soluble prodrug for the highly active, highly toxic, highly lipophilic CPT derivative, SN38 (10-hydroxy-7-ethyl-CPT). CPT-11 is an inactive compound, and requires activation by a putative carboxylesterase enzyme to the active SN38 species. It is also known that SN38 can undergo an additional glucuronidation reaction, in vivo, and that the SN38-glucuronide species may be highly toxic to normal, healthy cells, and has little antitumor activity.
Lipid soluble CPT derivatives have heretofore presented problems of formulation, administration and delivery to the patient. Because of CPT's poor water solubility, other solvents, such as sodium hydroxide, had to be employed in order to effectively deliver the drug as a solution, rather than a suspension, to the patient.
Some efforts to develop alternative formulations of highly lipophilic, poorly water soluble derivatives of Camptothecin (HLCDs) are disclosed in U.S. Pat. Nos. 5,447,936; 5,633,260; 5,674,273; and 5,674,274. The disclosures of these patents, commonly owned by the assignee of this invention, disclose the use of alternative solvents, dimethylacetamide (DMA) and dimethylisosorbide (DMI). U.S. patent application Ser. Nos. 08/461,385, filed Jun. 5, 1995, and 08/667,424, filed Jun. 21, 1996, disclose the use of N-methyl-pyrrolidin-2-one (NMP) as an alternative solvent for a number of HLCD formulations.